U.S. patent number 9,168,270 [Application Number 12/162,914] was granted by the patent office on 2015-10-27 for water-insoluble, iron-containing mixed metal, granular material.
This patent grant is currently assigned to OPKO IRELAND GLOBAL HOLDINGS, LTD.. The grantee listed for this patent is James David Morrison, Maurice Sydney Newton, Ruth Diane Pennel, Nigel Peter Rhodes, Alexis John Toft. Invention is credited to James David Morrison, Maurice Sydney Newton, Ruth Diane Pennel, Nigel Peter Rhodes, Alexis John Toft.
United States Patent |
9,168,270 |
Pennel , et al. |
October 27, 2015 |
Water-insoluble, iron-containing mixed metal, granular material
Abstract
There is provided a granular material comprising (i) at least
50% by weight based on the weight of the granular material of solid
water-insoluble mixed metal compound capable of binding phosphate
of formula (I):
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.ZH.sub.2O
(I) where M.sup.II is at least one of magnesium, calcium, lanthanum
and cerium; M.sup.III is at least iron(III); A.sup.n- is at least
one n-valent anion; x=.SIGMA.ny; 0<x.ltoreq.0.67,
0<y.ltoreq.1, and 0.ltoreq.z<10; (ii) from 3 to 12% by weight
based on the weight of the granular material of non-chemically
bound water, and (iii) no greater than 47% by weight based on the
weight of the granular material of excipient.
Inventors: |
Pennel; Ruth Diane (Wirral,
GB), Newton; Maurice Sydney (Sandbach, GB),
Morrison; James David (Northwich, GB), Toft; Alexis
John (Warrington, GB), Rhodes; Nigel Peter
(Warrington, GB) |
Applicant: |
Name |
City |
State |
Country |
Type |
Pennel; Ruth Diane
Newton; Maurice Sydney
Morrison; James David
Toft; Alexis John
Rhodes; Nigel Peter |
Wirral
Sandbach
Northwich
Warrington
Warrington |
N/A
N/A
N/A
N/A
N/A |
GB
GB
GB
GB
GB |
|
|
Assignee: |
OPKO IRELAND GLOBAL HOLDINGS,
LTD. (Grand Cayman, KY)
|
Family
ID: |
38006917 |
Appl.
No.: |
12/162,914 |
Filed: |
January 30, 2007 |
PCT
Filed: |
January 30, 2007 |
PCT No.: |
PCT/GB2007/000308 |
371(c)(1),(2),(4) Date: |
July 31, 2008 |
PCT
Pub. No.: |
WO2007/088343 |
PCT
Pub. Date: |
August 09, 2007 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20090317459 A1 |
Dec 24, 2009 |
|
Foreign Application Priority Data
|
|
|
|
|
Jan 31, 2006 [GB] |
|
|
0601899.8 |
Feb 28, 2006 [GB] |
|
|
0603984.6 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K
9/2077 (20130101); A61K 33/26 (20130101); A61K
9/1635 (20130101); A61K 33/24 (20130101); A61P
7/00 (20180101); A61K 9/2866 (20130101); A61K
9/16 (20130101); A61K 9/1611 (20130101); A61K
9/2846 (20130101); A61K 33/06 (20130101); A61K
33/244 (20190101); A61P 3/12 (20180101); A61K
9/1652 (20130101); A61K 33/24 (20130101); A61K
2300/00 (20130101); A61K 33/26 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
9/14 (20060101); A61K 9/16 (20060101); A61K
33/06 (20060101); A61K 33/26 (20060101); A61K
9/48 (20060101); A61K 9/28 (20060101); A61K
33/24 (20060101); A61K 9/20 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2061136 |
|
Jul 1971 |
|
DE |
|
3402878 |
|
Aug 1985 |
|
DE |
|
3801382 |
|
Aug 1989 |
|
DE |
|
0050792 |
|
May 1982 |
|
EP |
|
0134936 |
|
Mar 1985 |
|
EP |
|
0146410 |
|
Jun 1985 |
|
EP |
|
150792 |
|
Aug 1985 |
|
EP |
|
0368420 |
|
May 1990 |
|
EP |
|
0577294 |
|
Jan 1994 |
|
EP |
|
1304104 |
|
Apr 2003 |
|
EP |
|
1413197 |
|
Apr 2004 |
|
EP |
|
1707178 |
|
Oct 2006 |
|
EP |
|
1946750 |
|
Jul 2008 |
|
EP |
|
1214473 |
|
Apr 1960 |
|
FR |
|
2254556 |
|
Jul 1975 |
|
FR |
|
1336866 |
|
Nov 1973 |
|
GB |
|
2031395 |
|
Apr 1980 |
|
GB |
|
2254556 |
|
Oct 1992 |
|
GB |
|
173556 |
|
Aug 1979 |
|
HU |
|
201880 |
|
Jan 1990 |
|
HU |
|
63343 |
|
Apr 1995 |
|
IE |
|
61036222 |
|
Feb 1986 |
|
JP |
|
62145024 |
|
Jun 1987 |
|
JP |
|
0515576 |
|
Jun 1993 |
|
JP |
|
05155776 |
|
Jun 1993 |
|
JP |
|
5208816 |
|
Aug 1993 |
|
JP |
|
10059842 |
|
Mar 1998 |
|
JP |
|
10 101569 |
|
Apr 1998 |
|
JP |
|
10101569 |
|
Apr 1998 |
|
JP |
|
10236960 |
|
Sep 1998 |
|
JP |
|
3001114 |
|
Dec 1999 |
|
JP |
|
2000/086537 |
|
Mar 2000 |
|
JP |
|
2004 089760 |
|
Mar 2004 |
|
JP |
|
2004/089760 |
|
Mar 2004 |
|
JP |
|
97/48380 |
|
Dec 1997 |
|
PL |
|
189716 |
|
Jul 1999 |
|
PL |
|
200957 |
|
Sep 2001 |
|
PL |
|
414849 |
|
Sep 1977 |
|
SU |
|
91/18835 |
|
Dec 1991 |
|
WO |
|
9118835 |
|
Dec 1991 |
|
WO |
|
WO91/18835 |
|
Dec 1991 |
|
WO |
|
94/09798 |
|
May 1994 |
|
WO |
|
95/11033 |
|
Apr 1995 |
|
WO |
|
95/29679 |
|
Nov 1995 |
|
WO |
|
96/30029 |
|
Oct 1996 |
|
WO |
|
97/11166 |
|
Mar 1997 |
|
WO |
|
97/22266 |
|
Jun 1997 |
|
WO |
|
99/15189 |
|
Apr 1999 |
|
WO |
|
99/15189 |
|
Apr 1999 |
|
WO |
|
99/44580 |
|
Sep 1999 |
|
WO |
|
00/32189 |
|
Jun 2000 |
|
WO |
|
01/27069 |
|
Apr 2001 |
|
WO |
|
01/49301 |
|
Jul 2001 |
|
WO |
|
WO-03/013473 |
|
Feb 2003 |
|
WO |
|
03/017980 |
|
Mar 2003 |
|
WO |
|
03/028706 |
|
Apr 2003 |
|
WO |
|
03/072084 |
|
Sep 2003 |
|
WO |
|
03/092658 |
|
Nov 2003 |
|
WO |
|
2004/016553 |
|
Feb 2004 |
|
WO |
|
2004/018094 |
|
Mar 2004 |
|
WO |
|
2005/009381 |
|
Feb 2005 |
|
WO |
|
2005/018651 |
|
Mar 2005 |
|
WO |
|
2005/027876 |
|
Mar 2005 |
|
WO |
|
2006/085079 |
|
Aug 2006 |
|
WO |
|
WO2006/085079 |
|
Aug 2006 |
|
WO |
|
WO-2007/074909 |
|
Jul 2007 |
|
WO |
|
2007/088343 |
|
Aug 2007 |
|
WO |
|
WO-2007/135362 |
|
Nov 2007 |
|
WO |
|
Other References
Rudnic and Schwartz, Oral Solid Dosage Forms. Remington: The
Science and Practice of Pharmacy, 20th Edition. Gennaro, A.R. Ed.,
Lippincott Williams & Wilkins, Baltimore MD, (2000) Chapter 45,
pp. 858-893. cited by examiner .
Labajos et al. New layered double hydroxides with hydrotalcite
structure containing Ni(II) and V(III), Journal of Materials
Chemistry, 1999, 9, pp. 1033-1039. cited by examiner .
Rankin et al. "The development and in-vitro evaluation of novel
mixed metal hydoxy-carbonate compounds as phosphate binders",
Journal of Pharmacy and Pharmacology, 53, 2001, pp. 361-369. cited
by examiner .
Mesh to Micron Conversion Chart,
http://www.showmegold.org/news/Mesh.htm, accessed Sep. 27, 2012.
cited by examiner .
Naylor T.A. et al., Use of gastro-intestinal model and gastroplus
for the prediction of in vivo performance, Industrial Pharmacy,
Dec. 2006, issue 12, p. 9-12. cited by applicant .
Larsson M. et al., Estimation of the bioavailability of iron and
phosphorus in cereals using a dynamic in vitro gastrointestinal
model, J. Sci. Food Agric, 1997, vol. 74, p. 99-106. cited by
applicant .
Autissier V. et al., "Relative in vitro Efficacy of the Phosphate
Binders Lantanum Carbonate and Sevelamer Hydrochloride", Journal of
Pharmaceutical Sciences, 2007, vol. 96, No. 10., p. 2818-2826
(online publication date May 11, 2007, after application date).
cited by applicant .
Written Opinion of the International Searching Authority for
PCT/GB2007000308, Nov. 30, 2007. cited by applicant .
Abramowitz M. et al., Serum Alkaline Phosphatase and Phosphate and
Risk of Mortality and Hospitalization, Clin, J. Am. Soc. Nephrol,
2010 vol. 5, No. 6 p. 1064-1071. cited by applicant .
Schwarz S. et al., Association of Disorders in Mineral Metabolism
with Progression of Chronic Kidney Disease, Clin. J. Am. Soc.
Nephrol., 2006, vol. 1, p. 825-831. cited by applicant .
De Roy et al., "Layered Double Hydroxides: Synthesis and
Post-Synthesis Modification." Layered Double Hydroxides: Present
and Future, Nova Science Publishers Inc., New York, Chapter 1, pp.
1-37 (2001). cited by applicant .
Evans et al., "Structural Aspects of Layered Double Hydroxides."
Struct Bond, vol. 119, pp. 1-12 (2006). cited by applicant .
He et al., "Preparation of Layered Double Hydroxides." Struct Bond,
vol. 119, pp. 89-119 (2006). cited by applicant .
Loghman-Adham, "Safety of New Phosphate Binders for Chronic Renal
Failure." Drug Safety, vol. 26(15), pp. 1093-1115 (2003). cited by
applicant .
Rives, "Study of Layered Double Hydroxides by Thermal Methods."
Layered Double Hydroxides: Present and Future, Nova Science
Publishers Inc., New York, Chapter 4, pp. 116-133 (2001). cited by
applicant .
De Roy et al, "Anionic clays: Trends in pillaring chemistry,"
Synthesis of Microporous Materials, Chapter 7. cited by applicant
.
"Hydrothermal Methods" p. 108, In: Duan et al. (eds.), Layered
Double Hydroxides, Germany: Springer (2006). cited by applicant
.
Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery
Systems, Chapters 1-8 (pp. 1-243) Lippincott, Williams &
Wilkins (1999). cited by applicant .
Bejoy, Hydrotalcite: The Clay that Cures, Springer; Resonance, vol.
6 No. 2, pp. 57-61 (2001). cited by applicant .
Evonik Industries AG, product information for Eudragit.RTM. E100,
Eudragit.RTM. E POA and Eudragit.RTM. E 12,5; pp. 1-6 (Oct. 2011).
cited by applicant .
Adams et al., Formulation of a sterile surgical lubricant, J.
Pharm. Pharmacol., 24 Suppl:178P (1972). cited by applicant .
Hollander et al., Antacids vs. placebos in peptic ulcer therapy: a
controlled double-blind investigation, JAMA, 226(10):1181-5 (1973).
cited by applicant .
Hudson et al., Thermal conversion of a layered (Mg/Al) double
hydroxide to the oxide, J. Mater. Chem., 5(2):323-9 (1995). cited
by applicant .
International Preliminary Report on Patentability for corresponding
international application No. PCT/GB2011/050185, issuance date Aug.
7, 2012. cited by applicant .
International Search Report and Written Opinion for corresponding
international application No. PCT/GB2011/050185, mailing date Feb.
6, 2012. cited by applicant .
Mesh to Micron Conversion chart, retrieved from the Internet at
<http:///www.shomegold.org/news/Mesh.htm>, accessed Sep. 27,
2012. cited by applicant .
Rankin et al., The development and in-vitro evaluation of novel
mixed metal hydroxy-carbonate compounds as phosphate binders, J.
Pharm. Pharmacol., 53:361-9 (2001). cited by applicant .
Sigma-Aldrich product information for Iron(III) nitrate
nonanhydrate, retrieved from the Internet:
<http:www.sigmaaldrich.com> on Jun. 11, 2012 (one page).
cited by applicant .
Chitrikar et al, "Adsorption of phosphate from seawater on calcine
MgMn-layered double hydroxides," Journal of Colloid and Interface
Science, 2005, pp. 45-51, vol. 290. cited by applicant .
Hibino et al, "Calcination and rehydration behaviour of Mg--Fe--CO3
hydrotalcite-like compounds," Journal of Materials Science Letters,
2000, pp. 1403-1405, vol. 19. cited by applicant .
De Roy et al, "Layered double hydroxides: Synthesis and
post-synthesis modification," Calcination and Reconstruction, 2001,
p. 33, chap.1, Vincente Rives ed. cited by applicant .
Del Arco et al, "Effect of the Mg:Al ratio on borate (or
silicate)/nitrate exchange in hydrotalcite," Journai of Solid State
Chemistry, 2000, pp. 272-280, vol. 151. cited by applicant .
Frost et al, "Thermal decomposition of synthetic hydrotalcites
reevesite and pyroaurite," Journal of Thermal Analysis and
Calorimetry, 2004, pp. 217-225, vol. 76. cited by applicant .
Brouwers, "Liquid Antacids," Pharmaceutisch Weekblad, 1975, pp.
337-351, vol. 110 (abstract only). cited by applicant .
Li et al, "Stoichiometric synthesis of pure MFe2O4 (M=Mg, Co and
Ni) spinel ferrites from tailored layered double hydroxides
(hydrotalcite-like) precursors," Chem. Mater., 2004, pp. 1597-1602,
vol. 16. cited by applicant .
Meng et al, "Preparation and thermal decomposition of
magnesium/iron (III) layered double hydroxide intercalated by
hexacyanoferrate (III) ions," Journal of Materials Science, 2004,
pp. 4655-4657, vol. 39. cited by applicant .
Zhu et al, "Adsorption of phosphate by hydrotalcite and its
calcined product," Acta Mineralogica Sinica, Mar. 2005, vol. 25,
No. 1 (abstract only). cited by applicant .
Meng et al, "Preparation of magnetic material containing MgFe2O4
spinel ferrite from a Mg--Fe(III) layered double hydroxide
intercalated by hexacyanoferrate(III) ions," Materials Chemistry
and Physics, 2004, pp. 1-4, vol. 86. cited by applicant .
Kovanda et al, "Thermal behaviour of Ni--Mn layered double
hydroxide and characterization of formed oxides," Solid State
Sciences, 2003, pp. 1019-1026, vol. 5. cited by applicant .
Newman et al, "Comparative study of some layered hydroxide salts
containing exchangable interlayer anions," Journal of Solid State
Chemistry, 1999, pp. 26-40, vol. 148. cited by applicant .
Erickson et al, "A study of structural memory effects in synthetic
hydrotalcites using environmental SEM," 2005, pp. 226-229, vol. 59.
cited by applicant .
Miyata, "Physiochemical properties of synthetic hydrotalcites in
relation to composition," Clays and Clay Minerals, 1980, pp. 50-56,
vol. 28, No. 1. cited by applicant .
Barriga et al, "Hydrotalcites as sorbent for 2, 4,
6-trinitrophenol: influence of the layer composition and interlayer
anion," Journal of Materials Chemistry, 2002, pp. 1027-1034, vol.
12. cited by applicant .
Tichit et al, "Catalysis by hydrotalcites and related materials,"
Cattech, 2003, pp. 206-217, vol. 7, No. 6. cited by applicant .
Chatelet et al, "Competition between monovalent and divalent anions
for calcined and uncalcined hydrotalcite: anion exchange and
adsorption sites," Colloids and Surfaces: A Physiochemical and
Engineering Aspects 1996, pp. 167-175, vol. 111. cited by applicant
.
Rajamathi et al, "Reversable thermal behaviour of the layered
double hydroxide of Mg with Al," Mechanistic Studies, 2000, pp.
2754-2757, vol. 10. cited by applicant .
Lazaridis, "Sorption removal of anions and cations in single batch
systems by uncalcined and calcined Mg--Al--CO3 Hydrotalcite," Water
Air and Soil Pollution, 2003, pp. 127-139, vol. 146. cited by
applicant .
Bolognini et al, "Mg/Al mixed oxides prepared by coprecipitation
and sol-gel routes: a comparison of their physico-chemical features
and performances in m-cresol methylation," Microporous and
Mesoporous Materials, 2003, pp. 77-89, vol. 66. cited by applicant
.
Zhang et al, "Phosphorous anion exchange characteristic of a
pyroaurite-like compound," Inorganic Materials, Mar. 1997, vol. 4
(abstract only). cited by applicant .
Marchi et al, "Impregnation-induced memory effect of thermally
activated layered double hydroxide," Applied Clay Science, 1998,
pp. 35-48, vol. 13. cited by applicant .
Zhang et al, "Synthesis and characterisation of a novel nanoscale
magnetic solid base catalyst involving a layered double hydroxide
supported on a ferrite core," Journal of Solid State Chemistry,
2004, pp. 772-780, vol. 177. cited by applicant .
Badreddine et al, "Ion exchange of different phosphate ions into
the zinc--aluminium--chloride layered double hydroxide," Material
Letters, 1999, pp. 391-395, vol. 38. cited by applicant .
Sato et al, "Causticization of sodium carbonate with rock-salt type
magnesium aluminium oxide formed by the thermal decomposition of
hydrotalcite-like layered double hydroxide," J. Chem. Tech.
Biotechnol., 1993, pp. 137-140, vol. 57. cited by applicant .
Kokot et al, "A rotating disk study on the rates of hydrotalcite
dissolution at 25 degrees Celsius," Pharmazie, 1993, pp. 287-289,
vol. 48-H4. cited by applicant .
De Roy et al, "Anionic clays: Trends in pillaring chemistry,"
Synthesis of Microporous Materials, Chapter 7, 1992. cited by
applicant .
Pesic et al, "Thermal characteristics of a synthetic
hydrotalcite-like material," Journal of Materials Chemistry, 1992,
pp. 1069-1073, vol. 2, No. 10. cited by applicant .
Ferreria et al, "Thermal decomposition and structural
reconstruction effect on Mg Fe based hydrotalcite compounds,"
Journal of Solid State Chemistry, 2004, pp. 3058-3069, vol. 177.
cited by applicant .
Del Arco et al, "Surface and textural properties of
hydrotalcite-like materials and their decomposition products,"
Characterisation of porus solids III (studies in surface science
and catalysis), pp. 507-515, 1997 vol. 87. cited by applicant .
Ambrogi et al, "Intercalation compounds of hydrotalcite-like
anionic clays with anti-inflammatory agents, II: Uptake of
diclofenac for controlled release formulation," AAPS PharmSciTech,
2002, vol. 3, No. 3, art.26. cited by applicant .
Seida et al, "Removal of phosphate by layered double hydroxides
containing iron," Water Research, 2002, pp. 1306-1312, vol. 36.
cited by applicant .
Linares et al, "The influence of hydrotalcite and cancrinite-type
zeolite in acidic aspirin solutions," Microporous and Mesoporous
Materials, 2004, pp. 105-110, vol. 74. cited by applicant .
Lazaridis et al, "Flotation of metal loaded clay anion exchangers
Part I: The case of chromates," Chemosphere, 2001, pp. 373-378,
vol. 42. cited by applicant .
Lazaridis et al, "Flotation of metal loaded clay anion exchangers
Part II: The case of arsenates," Chemosphere, 2002, pp. 319-324,
vol. 47. cited by applicant .
Rubinstein et al, "The effect of granule size on the in vitro and
in vivo properties of bendrofluazide tablets 5mg," Pharm. Acta
Helv., 1977, vol. 52, Nos. 1/2. cited by applicant .
USANA Technical Bulletin, Tablet Excipients, Jun. 1999. cited by
applicant .
International Speciality Products, Pharmaceuticals Solid Dosage
Forms, 2004. cited by applicant .
Brauner, "Das atomgewicht des lanthans," Zeitschrift fur
Anorganische Chemie, 1902, pp. 317-321, vol. 33, No. 1. cited by
applicant .
International Preliminary Report on Patentabilty for
PCT/GB2006/000452, Aug. 14, 2007. cited by applicant .
Emmet, "A Comparison of Clinically Useful Phosphorus Binders for
Patients with Chronic Kidney Failure" Kidney International 2004,
pp. s25-s32, vol. 66, supp. 90. cited by applicant .
Ishimura et al, "Hyper- and Hypophosphataemia" Calcium in Internal
Medicine, 2001, (Morii ed.) (1st Ed. 2002) Chapter 4c pp. 149-158.
cited by applicant .
Spengler et al, "Cross-linked iron dextran is an efficient oral
phosphate binder in the rat," Nephrol. Dial. Transplant, 1996, pp.
808-812, vol. 11. cited by applicant .
Budavari et al eds. "The Merck Index," 1996, pp. 277, 331, 917,
Merck & Co., Inc. cited by applicant .
Ookubo et al, "Hydrotalcites as Potential Adsorbents of Intestinal
Phosphates," Journal of Pharmaceutical Sciences, Nov. 1992, pp.
1139-1140, vol. 81, No. 11. cited by applicant .
Raki et al, "Preparation, characterisation, and Mossbauer
spectroscopy of organic ion intercalated pyroaurite-like layered
double hydroxides," Chem. Matter, 1995, pp. 221-224, vol. 7. cited
by applicant .
Hansen et al, "Synthesis and characterisation of pyroaurite,"
Applied Clay Science, 1995, pp. 5-19, vol. 10. cited by applicant
.
Zhang et al, "Synthesis of Mg/Fe pyroaurite-like compounds and
their anion-exchange characteristics," Inorganic Materials, 1995,
pp. 480-485, 2:259. cited by applicant .
Reichle, "Synthesis of anionic clay materials (mixed metal
hydroxides, hydrotalcite)," Solid State Ionics, 1996, pp. 135-141,
vol. 22. cited by applicant .
Zhang et al, "Phosphorous anion-exchange characteristics of a
pyroaurite-like compound," Inorganic Materials, Mar. 1997. pp.
132-138, vol. 4. cited by applicant .
Ulibarri et al, "Kinetics of the thermal dehydration of some
layered hydroxycarbonates," Thermochimica Acta, 1998, pp. 231-236,
vol. 135. cited by applicant .
Trifiro et al, "Hydrotalcite-like Anionic Clays (Layered Double
Hydroxides)," pp. 251-291, 1996. cited by applicant .
"Merck Index," p. 969, entries 5694-5707, 1996. cited by applicant
.
Oe et al, "Long term use of magnesium hydroxide as a phosphate
binder in patients on hemodialysis," Clinical Nephrology, 1987, pp.
180-185, vol. 28, No. 4. cited by applicant .
Guillot et al, "The use of magnesium containing phosphate binders
in patients with end-stage renal disease on maintenance dialysis,"
Nephron, 1982, pp. 114-117, vol. 30. cited by applicant .
O'Donovan et al, "Substitution of aluminium salts by magnesium
salts in control of dialysis hyperphosphataemia," The Lancet, Apr.
19, 1986, pp. 880-881. cited by applicant .
Cook, "Adaptation in iron metabolism," A. J. Clin. Nutr., 1990, pp.
301-308, vol. 51. cited by applicant .
Bothwell, "Overview and mechanisms of iron regulation," Nutrition
Reviews, Sep. 1995, pp. 237-245, vol. 53. cited by applicant .
McCance et al, "Absorption and excretion of iron," The Lancet Sep.
18, 1937, pp. 680-684. cited by applicant .
Van Der Voet et al, "Intestinal Absorption of Aluminum from
Antacids: A Comparison Between Hydrotalcite and Algeldrate"
Clinical Toxicology, 1986-87, 24(6), pp. 545-553. cited by
applicant .
Powell et al, "The Chemistry Between Aluminum in the
Gastrointestinal Lumen and its Uptake and Absorption" Proceedings
of the Nutrition Society, 1993, pp. 241-253, vol. 52. cited by
applicant .
Carlino, "Chemistry between the sheets," Chemistry in Britain, Sep.
1997, pp. 59-62. cited by applicant .
Zhu et al, "Different Mg to Fe Ratios in the Mixed Metal Mg:Fe
Hydroxy-Carbonate Compounds with Established Phosphate Binders"
Journal of Pharmaceutical Sciences, 2002, pp. 53-66, vol. 91, No.
1. cited by applicant .
Grant & Hackh's Chemical Dictionary, Fifth Edition, McGraw
Hill, Inc., p. 571, 1987. cited by applicant .
Tezuka et al, "The synthesis and phosphate adsorptive properties of
Mg(II)--Mn(III) Layered Double Hydroxides and their heat-treated
materials," Bull Chem. Soc. Jpn., 2004, pp. 2101-2107, vol. 77.
cited by applicant .
Ookubu et al, "Preparations and Phosphate Ion Exchange Properties
of a Hydrotalcite Compound" Langmuir, 1993, pp. 1418-1422, vol. 9.
cited by applicant .
Hansen et al, "Formation of Synthetic Analogues of Double Metal
Hydroxy Carbonate Minerals under Controlled pH Conditions: I. The
Synthesis of Pyraurite and Revesite" Clay Minerals, 1990, pp.
161-179, vol. 25. cited by applicant .
Hansen et al, "The Use of Glycerol Intercalates in the Exchange of
CO3(-2) with SO4(-2), NO3--, or Cl-- in Pyroautrile-type Compounds"
Clay Minerals, 1991, pp. 311-327, vol. 26. cited by applicant .
Shin et al, "Phosphorus Removal by Hydrotalcite-like Compounds
(HTLcs)" Wat. Sci. Tech., 1996, pp. 161-168, vol. 34, Nos. 1-2.
cited by applicant .
Hashi et al, "Preparation and Properties of Pyroaurite-like Hydroxy
Minerals" Clays and Clay Minerals, 1983, pp. 152-154, vol. 31 No.
2. cited by applicant .
Playle et al, "The In-Vitro Antacid and Anti-Pepsin Activity of
Hydrotalacite" Pharm. Acta Helv., 1974, pp. 298-302 vol. 49(9/10).
cited by applicant .
Sato et al, "Adsorption of Various Anions by Magnesium Aluminum
Oxide Mg(0.7)Al(0.3)O(1.15)," Ind. Eng. Chem. Prod. Res. Dev.,
1986, pp. 89-92, vol. 25 (XP002392181). cited by applicant .
Rives, Ed., "Layered double hydroxides: present and future," Nova
Science, 2001, pp. 243-244, chap.8. cited by applicant .
Sheikh et al, "Reduction of Dietary Phosphorus Absorption by
Phosphorus Binders: A Theoretical, In Vitro, and In Vivo Study" J.
Clin. Invest. Jan. 1989, pp. 66-73, vol. 83. cited by applicant
.
Stamatakis et al., "Influence of pH on in vitro disintegration of
phosphate binders," American Journal of Kidney Disease, Nov. 1998,
pp. 808-812, vol. 32, No. 5. cited by applicant .
Badawy et al, "Effect of drug substance particle size on the
characteristics of granulation manufactured in a high shear mixer,"
AAPS PharmSciTech, 2000, 1(4) art.33. cited by applicant .
Roblot et al, "Effect of lubricant level and applied copressional
pressure on surface friction of tablets," Journal of Pharmaceutical
Sciences, Jun. 1985, vol. 74, No. 6. cited by applicant .
Bolhuis et al, "Interaction of tablet disintegrants and magnesium
strearate during mixing I: Effect on tablet disintegration,"
Journal of Pharmaceutical Sciences, Dec. 1981, pp. 1328-1330, vol.
70, No. 12. cited by applicant .
Kaplan et al, "A preference study: Calcium acetate tablets versus
gelcaps in hemodialysis patients," Nephrology Nursing Journal, Aug.
2002, vol. 29, No. 4. cited by applicant .
Murthy et al, "Effect of shear mixing on in vitro drug release of
capsule formulations containing lubricants," Journal of
Pharmaceutical Sciences, Sep. 1977, vol. 66, No. 9. cited by
applicant .
Leinonen et al, "Physical and lubrication properties of magnesium
stearate," Journal of Pharmaceutical Sciences, Dec. 1992, vol. 81,
No. 12. cited by applicant .
Suren, "Evaluation of lubricants in the development of tablet
formulation," Dansk Tidsskr. Farm., 1997, pp. 331-338, vol. 45.
cited by applicant .
Vitkova. "The use of some hydrophobic substances in tablet
technology," Milan Chilabala, Acta Pharmaceutica Hungaria 1998, pp.
336-344, vol. 68. cited by applicant .
Iranloye et al, "Effects of compression force, particle size and
lubricants on dissolution rate," Journal of Pharmaceutical
Sciences, Apr. 1978, pp. 535-539 vol. 64, No. 4. cited by applicant
.
Vatier, et al, "Antacid activity of calcium carbonate and
hydrotalcite tablets," Arzneim-Forsch/Drug Res., 1994, pp. 514-518,
vol. 44, No. 4. cited by applicant .
Brouwers et al, "De Invloed van de toedieningsvorm op de
werkingsduur en op het pH-Bereik bij antacida; een in-vitro en
in-vivo studie," Pharmaceutisch Weekblad, 1976, pp. 1244-1248, vol.
111 (abstract only). cited by applicant .
Brouwers et al, "Biopharmaceutical tests on antacids: In vitro and
in vivo studies," Drugs under experimental and clinical research,
1997, pp. 55-61, vol. 5. cited by applicant .
Miederer et al, "Acid neutralization and bile acid binding capacity
of hydrocalcite compared with other antacids: An in vitro study,"
Chinese Journal of Digestive Diseases, Oct. 2003, pp. 140-146, vol.
4, No. 3. cited by applicant .
Llewellyn et al, "The binding of bile acids by hydrocalcite and
other antacid preparations," Pharmaceutica Acta Helvetiae, 1977,
pp. 1-5, vol. 52, No. 1/2. cited by applicant .
Li et al, "Enteric coated layered double hydroxides as a controlled
release drug delivery system," International Journal of
Pharmaceutics, 2004, pp. 89-95, vol. 287. cited by applicant .
Aoshima et al, "Glycerin fatty acids esters as a new lubricant of
tablets," International Journal of Pharmaceutics, 2005, pp. 25-34,
vol. 293. cited by applicant .
Das et al., Adsorption of phosphate by layered double hydroxides in
aqueous solutions, Appl. Clay Sci., 32(3-4:252-60 (2006). cited by
applicant .
Dewberry et al., "Lanthanum carbonate: A novel non-calcium
containing phosphate binder", J Am Soc Nephrol, 8:A2610 (1997).
cited by applicant .
Entry for "obtainable", Collins English Dictionary, retrieved from
the Internet at <http://www.collinsdictionary.com> on May 15,
2013. cited by applicant .
Fernandez et al., The effect of iron on the crystalline phases
formed upon thermal decomposition of Mg--Al--Fe hydrotalcites, RCS
Publishing: Journal of Materials Chemistry, 8(11):2507-14 (1998).
cited by applicant .
Forano, Environmental remediationinvolving layered double
hydroxides, pp. 426-458, vol. 1, Elsevier Interface Science and
Technology (2004). cited by applicant .
Goh et al., Application of layered double hydroxides for removal of
oxyanions: a review, Water Res., 42:1343-68 (2008). cited by
applicant .
Grubel et al., Interaction of an aluminum--magnesium containing
antacid and gastric mucus: possible contribution to the
cytoprotective function of antacids, Aliment. Pharmacol. Ther.,
11(1):139-45 (1997). cited by applicant .
Hansen et al., Reduction of nitrate to ammonium by sulphate green
rust: activation energy and reaction mechanism, Clay Minerals,
33:87-101 (1998). cited by applicant .
Hirahara et al., Synthesis and antacid property of Mg--Fe layered
double hydroxide, Nendo Kagaku--J. Clay Sci. Soc. of Japan,
42(2):70-6 (2002). cited by applicant .
Konorev et al., Selection of the optimal antacid drug in clinical
practice, Consilium Medicum, vol. 5, pp. 1-10 (2003). cited by
applicant .
Kostura et al., Rehydration of calcined Mg--Al hydrotalcite in
acidified chloride-containing aqueous solution, Collect. Czech.
Chem. Commun., 72:1284-94 (2007). cited by applicant .
Merriam-Webster's Collegiate Dictionary--11th edition, entry for
"prophylaxis" on p. 996 (2004). cited by applicant .
Toth et al., Nano-scaled inorganic/biopolymer composites: molecular
modeling vistas, AIChE Annual Meeting (2005). cited by applicant
.
Toth et al., Structure and energetics of biocompatible polymer
nanocomposite systems: a molecular dynamics study,
Biomacromolecules, 7:1714-9 (2006). cited by applicant .
Tsuji et al., Hydrotalcites with an extended
A1.sup.3+-substitution: synthesis, simultaneous TG-DTA-MS study,
and their CO.sub.2 adsorption behaviors, J. Mater. Res.,
8(5):1137-42 (1993). cited by applicant .
Cargill et al., Chemical reactivity of aluminium-based
pharmaceutical compounds used as phosphate-binders, J. Pharm.
Pharmacol., 41:11-16 (1989). cited by applicant .
Remuzzi et al., Hematologic consequences of renal failure, Chapter
50, pp. 2079-2102 In: Rose, Pathophysiology of Renal Disease,
McGraw-Hill (1987). cited by applicant.
|
Primary Examiner: Barham; Bethany
Assistant Examiner: Javier; Melissa
Attorney, Agent or Firm: Marshall, Gerstein & Borun
LLP
Claims
The invention claimed is:
1. A dried granular material comprising granules, each granule
comprising a mixture of (i) at least 50% by weight based on the
weight of the granule of solid water-insoluble inorganic mixed
metal compound capable of binding phosphate and which contains iron
(III) and at least one of magnesium, calcium, lanthanum or cerium,
wherein the mixed metal compound is not a hydrothermally-treated
compound, (ii) from 3 to 10% by weight based on the weight of the
granule of non-chemically bound water, and (iii) an excipient,
present in an amount no greater than 47% by weight based on the
weight of the granule, wherein at least 50% by weight of the
granules of the granular material have a diameter of from 106
micrometers to 1180 micrometers.
2. A granular material according to claim 1 wherein the mixed metal
compound comprises a layered double hydroxide.
3. A granular material according to claim 1 wherein the mixed metal
compound contains at least one of hydroxyl and carbonate ions and
contains as the metals iron (III) and magnesium.
4. A granular material according to claim 1, wherein the granular
material comprises from 5 to 20% by weight of pregelatinised starch
as excipient based on the weight of the granule.
5. A granular material according to claim 1, comprising from 1 to
15% by weight of cross linked polyvinyl pyrrolidone as excipient
based on the weight of the granule.
6. A granular material according to claim 1 wherein the excipient
comprises at least pregelatinised starch and crospovidone.
7. A granular material according to claim 1 wherein at least 95% by
weight of the granules of the granular material have a diameter
less than 1180 micrometers.
8. A unit dose for oral administration comprising a water resistant
capsule containing a granular material according to claim 1.
9. A unit dose for oral administration comprising a compacted
tablet of a granular material according to claim 1.
10. A unit dose according to claim 9 further comprising a lubricant
between the granules.
11. A unit dose according to claim 10 wherein the lubricant is or
comprises magnesium stearate.
12. A unit dose according to claim 9 coated with a water-resistant
coating.
13. A unit dose according to claim 12 wherein the water-resistant
coating comprises at least 30% by weight of a butylated
methacrylate copolymer.
14. A unit dose according to claim 12 wherein the tablet has a
belly band having a width of 2 mm or more.
15. A unit dose according to claim 8 wherein the solid
water-insoluble inorganic compound capable of binding phosphate is
present in an amount of at least 200 mg.
16. A process for the preparation of a granular material as defined
in claim 1 comprising the steps of: i) mixing the solid
water-insoluble inorganic mixed metal compound with one or more
excipients to produce a homogeneous mix, ii) contacting a suitable
liquid with the homogeneous mix and mixing in a granulator to form
wet granules, iii) optionally passing the wet granules though a
screen to remove granules lager than the screen size, iv) drying
the wet granules to provide dry granules, and v) milling and/or
sieving the dry granules, wherein at least 50% by weight of the
granules of the granular material have a diameter of from 106
micrometers to 1180 micrometers.
17. A process according to claim 16 where in the liquid is selected
from water, ethanol and mixtures thereof.
18. A method of treating hyperphosphataemia comprising
administering a granular material according to claim 1 to a patient
in need thereof.
Description
FIELD
The present invention relates to granules containing
water-insoluble inorganic solids, particularly mixed metal
compounds, having pharmaceutical activity, as phosphate binders. It
also extends to methods of manufacture of the granules and their
use in unit doses for oral administration.
BACKGROUND
Various ailments may lead to high phosphate concentrations in the
blood in animals, particularly warm-blooded animals such as humans.
This can lead to a number of physiological problems, such as
deposition of calcium phosphate.
In patients with kidney failure who are being treated by regular
haemodialysis, phosphate concentrations in the blood plasma can
rise dramatically and this condition, known as hyperphosphataemia,
can result in calcium phosphate deposition in soft tissue. Plasma
phosphate levels may be reduced by oral intake of inorganic and
organic phosphate binders.
Classes of inorganic solid phosphate binders are disclosed in WO
99/15189. These include alkali treated inorganic sulphates, such as
calcium sulphate, and mixed metal compounds which are substantially
free from aluminium and which have a phosphate binding capacity of
at least 30% by weight of the total weight of phosphate present,
over a pH range of from 2-8, as measured by the phosphate binding
test as described therein. The inorganic solids are water insoluble
and are primarily intended for oral administration.
Typically such mixed metal compounds may contain iron (III) and at
least one of magnesium, calcium, lanthanum and cerium. Preferably
they also contain at least one of hydroxyl and carbonate anions and
optionally additionally, at least one of sulphate, chloride and
oxide.
Mixed metal compounds such as described in WO 99/15189 present
particular problems in the formulation of unit dosages containing
them. In part, these problems arise from the fact that the
compounds need to be dosed in relatively large amounts. This means
that in order for a unit dose to be of a size which does not make
it too difficult to swallow, assisting with patient compliance, the
inclusion level of the active ingredient needs to be quite high,
leaving very little formulation space for excipients.
There is a need for unit doses containing such inorganic solid
phosphate binders which include high levels of the pharmaceutically
active ingredient yet which maintain physical integrity and
stability on storage. There is also a need for such unit doses to
disintegrate in order to release the solid inorganic phosphate
binder in the stomach and to give rapid phosphate binding, but not
to disintegrate excessively in the mouth or oesophagus resulting in
an unpleasant taste and potential lack of patient compliance. There
is also a need for processing routes for forming the solid
inorganic phosphate binders into unit doses without problems caused
by poor flowability of the material and yet without excessive
hindering of the rate of phosphate binding for the material.
SUMMARY OF INVENTION
Thus, a first aspect of the present invention provides a granular
material comprising (i) at least 50% by weight based on the weight
of the granular material of solid water-insoluble mixed metal
compound capable of binding phosphate of formula (I):
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.zH.sub.2O
(I) where M.sup.II is at least one of magnesium, calcium, lanthanum
and cerium; M.sup.III is at least iron(III); A.sup.n- is at least
one n-valent anion; x=.SIGMA.ny; 0<x.ltoreq.0.67,
0<y.ltoreq.1, and 0<z.ltoreq.10; (ii) from 3 to 12% by weight
based on the weight of the granular material of non-chemically
bound water, and (iii) no greater than 47% by weight based on the
weight of the granular material of excipient.
A second aspect of the invention provides a unit dose for oral
administration comprising a water-resistant capsule containing
granules according to the first aspect of the invention.
A third aspect of the invention provides a unit dose for oral
administration comprising a compacted tablet of granules according
to the first aspect of the invention. Preferably, the tablet is
coated with a water-resistant coating.
The solid water-insoluble inorganic compound capable of binding
phosphate is referred to herein as an "inorganic phosphate binder"
or as "binder".
References herein to "granules" equally apply to the "granular
material" of the present invention.
It has been found that surprisingly, for such granules for use in
unit doses, the level of water is critical in maintaining the
physical integrity of the granules, and of unit doses prepared from
the granules during storage. Correct levels of water provide good
phosphate binding when the granules are ingested, without excessive
break-up of the granules or of tablets formed from the granules in
the mouth. It has also been found that such granules bind phosphate
rapidly.
It has also been found that by providing the compound of formula I
is a granular form rather that as a powder the flowability problems
of powders and the storage stability problems of powder based
tablets are overcome while the advantages of such systems with
regard to rapid disintegration are maintained. Fine particle size,
for example as found in powders, results in very poor flowability
of the powder resulting in poor tablet compression (tablets too
soft and not homogenous), poor storage stability and problems with
equipment loading. Surprisingly, we have found that by first
increasing the particle size of the finely divided particulate by
granulation of the mixture of compound of formula I with
excipients, drying the granules to a controlled moisture content
and reducing the granule size back down again to a more finely
divided particulate (such as the `small` particle size distribution
of Table 7) we can obtain suitable phosphate binding granules
without requiring substantial increased levels of excipients whilst
enabling operation of tablet compression machines typically capable
of commercial production rates (for example from 10,000 to 150,000
tablets/hour) and compression into a suitably shaped tablet of a
compact size which is not too difficult to swallow. In contrast,
typical tablet formulations such as those disclosed in U.S. Pat.
No. 4,415,555 or U.S. Pat. No. 4,629,626 Miyata et al of
hydrotalcite materials resulted in formulations comprising less
than 50% of the active compound and/or requiring hydrothermal
treatment of the hydrotalcite to increase storage stability of the
tablets.
The water content of the granules of the present invention is
expressed in terms of the content of non-chemically bound water in
the granules. This non-chemically bound water therefore excludes
chemically bound water. Chemically bound water may also be referred
to as structural water.
The amount of non-chemically bound water is determined by
pulverizing the granules, heating at 105.degree. C. for 4 hours and
immediately measuring the weight loss. The weight equivalent of
non-chemically bound water driven off can then be calculated as a
weight percentage of the granules.
It has been found that if the amount of non-chemically bound water
is less than 3% by weight of the granules, tablets formed from the
granules become brittle and may break very easily. If the amount of
non-chemically bound water is greater than 10% by weight of the
granules, disintegration time of the granules and of tablets
prepared from the granules increases, with an associated reduction
in phosphate binding rate and the storage stability of the tablet
or granules becomes unacceptable leading to crumbling on
storage.
By water-insoluble phosphate binder, it is meant that the binder
has a solubility in distilled water at 25.degree. C. of 0.5 g/liter
or less, preferably 0.1 g/liter or less, more preferably 0.05
g/liter or less.
The water-resistant capsule of the second aspect of the invention
is suitably a hard gelatine capsule. For the water-resistant
capsule, by water-resistant it is meant that on storage for 4 weeks
at 40.degree. C. and 70% relative humidity, the water uptake of the
unit dose, (i.e. the capsule containing the granules of the first
aspect of the invention), due to moisture content change is
preferably less than 10% more preferably less than 5% by weight of
the unit dose. Such capsules have the advantage of helping
stabilise the moisture content of the granules on storage
The tablets of third aspect of the invention preferably have a
water-resistant coating in order to inhibit moisture ingress into
the tablet or moisture loss from the tablet on storage. However,
the water resistant coating must allow break-up of the tablet after
a suitable time following ingestion such that the inorganic solid
phosphate binder can be effective in the gut of the patient. By
water-resistant it is meant that on storage for 4 weeks at
40.degree. C. and 70% relative humidity, the water uptake of the
coated tablet due to moisture content change is preferably less
than 10% more preferably less than 5% by weight of the coated
tablet. In a preferred aspect by water-resistant it is meant that
on storage for 12 months at 25.degree. C. and 60% relative
humidity, the water uptake of the coated tablet due to moisture
content change is preferably less than 10% more preferably less
than 5% by weight of the coated tablet. In a further preferred
aspect by water-resistant it is meant that on storage for 12 months
at 30.degree. C. and 65% relative humidity, the water uptake of the
coated tablet due to moisture content change is preferably less
than 10% more preferably less than 5% by weight of the coated
tablet. In a preferred aspect by water-resistant it is meant that
on storage for 6 months at 40.degree. C. and 75% relative humidity,
the water uptake of the coated tablet due to moisture content
change is preferably less than 10% more preferably less than 5% by
weight of the coated tablet.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
Phosphate Binders
By binding of phosphate ions, it is meant that the phosphate ions
are removed from solution and are immobilised in the atomic
structure of the water-insoluble inorganic solid phosphate
binder.
Suitable water-insoluble inorganic solids for binding phosphate
ions from solution (hereinafter also called inorganic phosphate
binders or as binders for brevity) are disclosed for instance in WO
99/15189 and include sulphates such as calcium sulphate, which has
been alkali treated, mixtures of different metal salts and mixed
metal compounds as described below. Preferred water-insoluble
inorganic solids for use as phosphate binders in the tablets of the
invention are mixed metal compounds.
Because of their water-insolubility, it is preferred if the
inorganic phosphate binders used in the tablets of the invention
are in a finely divided particulate form such that an adequate
surface area is provided over which phosphate binding or
immobilisation can take place. Suitably, the inorganic phosphate
binder particles have a weight median particle diameter (d.sub.50)
of from 1 to 20 micrometers, preferably from 2 to 11 micrometers.
Preferably, the inorganic phosphate binder particles have a
d.sub.90 (i.e. 90% by weight of the particles have a diameter less
than the d.sub.90 value) of 100 micrometers or less.
Mixed Metal Binders
The present invention provides a granular material comprising (i)
at least 50% by weight based on the weight of the granular material
of solid mixed metal compound capable of binding phosphate of
formula (I):
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.zH.sub.2O
(I) where M.sup.II is at least one of magnesium, calcium, lanthanum
and cerium; M.sup.III is at least iron(III); A.sup.n- is at least
one n-valent anion; x=.SIGMA.ny; 0<x.ltoreq.0.67,
0<y.ltoreq.1, and 0.ltoreq.z.ltoreq.10; (ii) from 3 to 12% by
weight based on the weight of the granular material of
non-chemically bound water, and (iii) no greater than 47% by weight
based on the weight of the granular material of excipient. The
present invention further provides a unit dose for oral
administration comprising a water-resistant capsule containing the
granular material. The present invention yet further provides a
unit dose for oral administration comprising a compacted tablet of
the granular material. Preferably, the tablet is coated with a
water-resistant coating.
A preferred inorganic phosphate binder is solid water-insoluble
mixed compound of formula (I):
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.zH.sub.2O
(1) where M.sup.II is at least one bivalent metal; M.sup.III is at
least one trivalent metal; A.sup.n- is at least one n-valent anion;
x=.SIGMA.ny and x, y and z fulfil 0<x.ltoreq.0.67,
0<y.ltoreq.1, 0.ltoreq.z.ltoreq.10.
In one preferred aspect 0.1<x, such as 0.2<x, 0.3<x,
0.4<x, or 0.5<x. In one preferred aspect 0<x.ltoreq.0.5.
It will be understood that x=[M.sup.III]/([M.sup.II]+[M.sup.III])
where [M.sup.II] is the number of moles of M.sup.II per mole of
compound of formula I and [M.sup.III] is the number of moles of
M.sup.III per mole of compound of formula I.
In one preferred aspect 0<y.ltoreq.1. Preferably
0<y.ltoreq.0.8. Preferably 0<y.ltoreq.0.6. Preferably
0<y.ltoreq.0.4. Preferably 0.05<y.ltoreq.0.3. Preferably
0.05<y.ltoreq.0.2. Preferably 0.1<y.ltoreq.0.2. Preferably
0.15<y.ltoreq.0.2.
In one preferred aspect 0.ltoreq.z.ltoreq.10. Preferably
0.ltoreq.z.ltoreq.8. Preferably 0.ltoreq.z.ltoreq.6. Preferably
0.ltoreq.z.ltoreq.4. Preferably 0.ltoreq.z.ltoreq.2. Preferably
0.1.ltoreq.z.ltoreq.2. Preferably 0.5.ltoreq.z.ltoreq.2. Preferably
1.ltoreq.z.ltoreq.2. Preferably 1.ltoreq.z.ltoreq.1.5. Preferably
1.ltoreq.z.ltoreq.1.4. Preferably 1.2.ltoreq.z.ltoreq.1.4.
Preferably z is approximately 1.4.
Preferably, 0<x.ltoreq.0.5, 0<y.ltoreq.1, and
0.ltoreq.z.ltoreq.10.
It will be appreciated that each of the preferred values of x, y
and z may be combined. Thus any combination of each of the values
listed in the table below are specifically disclosed herein and may
be provided by the present invention.
TABLE-US-00001 x y z 0.1 < x 0 < y .ltoreq. 0.8 0 .ltoreq. z
.ltoreq. 10 0.2 < x 0 < y .ltoreq. 0.6 0 .ltoreq. z .ltoreq.
8 0.3 < x 0 < y .ltoreq. 0.4 0 .ltoreq. z .ltoreq. 6 0.4 <
x 0.05 < y .ltoreq. 0.3 0 .ltoreq. z .ltoreq. 4 0.5 < x 0.05
< y .ltoreq. 0.2 0 .ltoreq. z .ltoreq. 2 0 < x .ltoreq. 0.67
0.1 < y .ltoreq. 0.2 0.1 .ltoreq. z .ltoreq. 2 0 < x .ltoreq.
0.5 0.15 < y .ltoreq. 0.2 0.5 .ltoreq. z .ltoreq. 2 1 .ltoreq. z
.ltoreq. 2 1 .ltoreq. z .ltoreq. 1.5 1 .ltoreq. z .ltoreq. 1.4 1.1
.ltoreq. z .ltoreq. 1.4
In the above formula (I), when A represents more than one anion,
the valency (n) of each may vary. ".SIGMA.ny" means the sum of the
number of moles of each anion multiplied by its respective
valency.
In formula (I), M.sup.II is preferably selected from Mg (II), Zn
(II), Fe (II), Cu (II), Ca (II), La (II) and Ni(II). Of these, Mg
is especially preferred. M.sup.III is preferably selected from
Mn(III), Fe(III), La(III), Ni (III) and Ce(III). Of these, Fe(III)
is especially preferred. Herein, (II) means a metal in a divalent
state and (III) means a metal in a trivalent state.
A.sup.n- is preferably selected from one or more of carbonate,
hydroxycarbonate, oxo-anions (eg. nitrates, sulphate),
metal-complex anion (eg. ferrocyanide), polyoxo-metalates, organic
anions, halide, hydroxide and mixtures thereof. Of these, carbonate
is especially preferred.
Preferably, the compound comprises less than 200 g/kg of Aluminium,
more preferably less than 100 g/kg, even more preferably less than
50 g/kg expressed as weight of aluminium metal per weight of
compound.
More preferably, only low levels of aluminium are present such as
less than 10 g/kg, preferably less than 5 g/kg.
Even more preferably, the compound is free from aluminium (Al). By
the term "free from aluminium" it is meant that the material termed
"free from aluminium" comprises less than 1 g/kg, more preferably
less than 500 mg/kg, even more preferably less than 200 mg/kg, most
preferably less than 120 mg/kg expressed as weight of elemental
aluminium per weight of compound.
Suitably the compound contains iron(III) and at least one of
Magnesium, Calcium, Lanthanum or Cerium, more preferably at least
one of Magnesium, Lanthanum or Cerium, most preferably
Magnesium.
Preferably, the compound comprises less than 100 g/kg of calcium,
more preferably less than 50 g/kg, even more preferably less than
25 g/kg expressed as weight of elemental calcium per weight of
compound.
More preferably, only low levels of calcium are present such as
less than 10 g/kg, preferably less than 5 g/kg.
Even more preferably, the compound is free from calcium. By the
term "free from calcium" it is meant that the material termed "free
from calcium" comprises less than 1 g/kg, more preferably less than
500 mg/kg, even more preferably less than 200 mg/kg, most
preferably less than 120 mg/kg expressed as weight of elemental
calcium per weight of material.
Preferably, the binder compound is free from calcium and free from
aluminium.
The final unit dose, comprising granules and any other material
making up the final unit dose, as a whole, is also preferably free
from aluminium and/or preferably free from calcium, using the
definitions as detailed above.
Preferably the solid mixed metal compound comprises at least some
material which is a Layered Double Hydroxide (LDH). More
preferably, the mixed metal compound of formula (I) is a layered
double hydroxide. As used herein, the term "Layered Double
Hydroxide" is used to designate synthetic or natural lamellar
hydroxides with two different kinds of metallic cations in the main
layers and interlayer domains containing anionic species. This wide
family of compounds is sometimes also referred to as anionic clays,
by comparison with the more usual cationic clays whose
interlamellar domains contain cationic species. LDHs have also been
reported as hydrotalcite-like compounds by reference to one of the
polytypes of the corresponding [Mg--Al] based mineral.
A particularly preferred mixed metal compound contains at least one
of carbonate ions, and hydroxyl ions.
A particularly preferred compound contains as M.sup.II and
M.sup.III, magnesium and iron (III) respectively.
The solid mixed metal compound or compounds may be suitably made by
co-precipitation from a solution, e.g. as described in WO 99/15189,
followed by centrifugation or filtration, then drying, milling and
sieving. The mixed metal compound is then rewetted again as part of
the wet-granulation process and the resulting granules dried in a
fluid-bed. The degree of drying in the fluid-bed is used to
establish the desired water content of the final tablet.
Alternatively, mixed metal compound may be formed by heating an
intimate mixture of finely divided single metal salts at a
temperature whereby solid-solid reaction can occur, leading to
mixed metal compound formation.
The solid mixed metal compound of formula (I) may be calcined by
heating at temperatures in excess of 200.degree. C. in order to
decrease the value of z in the formula. In this case, it may be
necessary to add water after calcination and prior to incorporation
of the solid mixed metal compound in the granules in order to
achieve the desired non-chemically bound water content of the
granules.
It will be appreciated by those skilled in the art that the water
provided by zH.sub.2O in formula (I) may provide part of the 3 to
12% by weight of non-chemically bound water (based on the weight of
the granular material). One skilled in the art may readily
determine the value of z based on standard chemical techniques.
Once the material of the present invention has been provided the
amount of the non-chemically bound water may then also be readily
determined in accordance with the procedure described herein.
By mixed metal compound, it is meant that the atomic structure of
the compound includes the cations of at least two different metals
distributed uniformly throughout its structure. The term mixed
metal compound does not include mixtures of crystals of two salts,
where each crystal type only includes one metal cation. Mixed metal
compounds are typically the result of coprecipitation from solution
of different single metal compounds in contrast to a simple solid
physical mixture of 2 different single metal salts. Mixed metal
compounds as used herein include compounds of the same metal type
but with the metal in two different valence states e.g. Fe(II) and
Fe(III) as well as compounds containing more than 2 different metal
types in one compound.
The mixed metal compound may also comprise amorphous
(non-crystalline) material. By the term amorphous is meant either
crystalline phases which have crystallite sizes below the detection
limits of x-ray diffraction techniques, or crystalline phases which
have some degree of ordering, but which do not exhibit a
crystalline diffraction pattern and/or true amorphous materials
which exhibit short range order, but no long-range order.
The compound of formula I is preferably formed with no aging or
hydrothermal treatment to avoid the crystals of the compound
growing in size and to maintain a high surface area over which
phosphate binding can take place. The unaged compound of formula I
is also preferably maintained in a fine particle size form during
the post-synthesis route to maintain good phosphate binding.
Phosphate Binding
Any reference herein to phosphate binding capacity means phosphate
binding capacity as determined by the following method, unless
otherwise specified.
40 mmoles/liter Sodium Phosphate solution (pH 4) is prepared and
treated with the phosphate-binder. The filtered solution of the
treated phosphate solution is then diluted and analysed by ICP-OES
for phosphorus content.
Reagents used for this method are: Sodium Dihydrogen Phosphate
Monohydrate (BDH, AnalaR.TM. grade), 1M hydrochloric acid,
AnalaR.TM. water), standard phosphorous solution (10,000 .mu.g/ml,
Romil Ltd), sodium chloride (BDH).
Specific apparatus used are: Rolling hybridisation incubator or
equivalent (Grant Boekal HIW7), 10 ml blood collection tubes,
Reusable Nalgene screw cap tubes (30 ml/50 ml), 10 ml disposable
syringes, 0.45 .mu.m single use syringe filter, ICP-OES
(inductively coupled plasma--optical emission spectrometer).
Phosphate solution is prepared by weighing 5.520 g (.+-.0.001 g) of
sodium di-hydrogen phosphate followed by addition of some
AnalaR.TM. water and transferring to a 1 ltr volumetric flask.
To the 1 liter volumetric flask is then added 1 M HCl drop-wise to
adjust the pH to pH 4 (.+-.0.1) mixing between additions. The
volume is then accurately made up to one liter using AnalaR.TM.
water and mixed thoroughly.
NaCl solution is prepared by accurately weighing out 5.85 g
(.+-.0.02 g) of NaCl and quantitatively transferring into a 1 liter
volumetric flask after which the volume is made up with AnalaR.TM.
water and mixed thoroughly.
Calibration Standards are prepared by pipetting into 100 ml
volumetric flasks the following solutions:
TABLE-US-00002 Flask No. 1 2 3 4 Identification Blank Std 1 Std 2
Std 3 NaCl solution 10 ml 10 ml 10 ml 10 ml 10000 ppm P Std 0 ml 4
ml 2 ml 1 ml (400 ppm) (200 ppm) (100 ppm)
The solutions are then made up to volume with AnalaR.TM. water and
thoroughly mixed. These solutions are then used as calibration
standards for the ICP-OES apparatus. The phosphate binder samples
are then prepared in accordance with the procedure described
hereafter and measured by ICP-OES. The ICP-OES results are
initially expressed as ppm but can be converted to mmol using the
equation: mmol=(reading ICP-OES in ppm/molecular weight of the
analyte).times.4 (dilution factor).
Aliquots of each test sample, each aliquot containing 0.5 g of the
phosphate binder, are placed into 30 ml screw top Nalgene tubes. If
the test sample is a unit dose comprising 0.5 g of the phosphate
binder, it may be used as such. All samples are prepared in
duplicate. 12.5 ml aliquots of the Phosphate solution are pipetted
into each of the screw top tubes containing the test samples and
the screw cap fitted. The prepared tubes are then placed into the
roller incubator pre heated to 37.degree. C. and rotated at full
speed for a fixed time such as 30 minutes (other times may be used
as shown in the Examples). The samples are subsequently removed
from the roller incubator, filtered through a 0.45 .mu.m syringe
filter, and 2.5 ml of filtrate transferred into a blood collection
tube. 7.5 ml of AnalaR.TM. water is pipetted into each 2.5 ml
aliquot, and mixed thoroughly. The solutions are then analysed on
the ICP-OES. The phosphate binding capacity is determined by:
phosphate binding (%)=100-(T/S.times.100)
where
T=Analyte value for phosphate in solution after reaction with
phosphate binder.
S=Analyte value for phosphate in solution before reaction with
phosphate binder.
Suitably, the water-insoluble inorganic solid phosphate binders
used in the granules of the present invention provide a phosphate
binding capacity for the material as measured by the above method
of at least 30% after 30 minutes, preferably at least 30% after 10
minutes, more preferably at least 30% after 5 minutes. Preferably
the water-insoluble inorganic solid phosphate binders used in the
tablets of the present invention have a phosphate binding capacity
as measured by the above method of at least 40% after 30 minutes,
preferably at least 30% after 10 minutes, more preferably at least
30% after 5 minutes. Even more preferably the water-insoluble
inorganic solid phosphate binders used in the tablets of the
present invention have a phosphate binding capacity as measured by
the above method of at least 50% after 30 minutes, preferably at
least 30% after 10 minutes, more preferably at least 30% after 5
minutes.
The pH of the phosphate binding measurement may be varied by use of
addition of either 1 M HCl or NaOH solution. The measurement may
then be used to assess the phosphate binding capacity at varying pH
values.
Suitably, the water-insoluble inorganic solid phosphate binders
used in the tablets of the present invention have a phosphate
binding capacity at a pH from 3 to 6, preferably at a pH from 3 to
9, more preferably at a pH from 3 to 10, most preferably at a pH
from 2 to 10, as measured by the above method, of at least 30%
after 30 minutes, preferably at least 30% after 10 minutes, more
preferably at least 30% after 5 minutes.
Preferably the water-insoluble inorganic solid phosphate binders
used in the tablets of the present invention have a phosphate
binding capacity at a pH from 3 to 4, preferably from 3 to 5, more
preferably from 3 to 6 as measured by the above method of at least
40% after 30 minutes, preferably at least 40% after 10 minutes,
more preferably at least 40% after 5 minutes.
Even more preferably the water-insoluble inorganic solid phosphate
binders used in the tablets of the present invention have a
phosphate binding capacity at a pH from 3 to 4, preferably from 3
to 5, more preferably from 3 to 6, as measured by the above method,
of at least 50% after 30 minutes, preferably at least 50% after 10
minutes, more preferably at least 50% after 5 minutes.
It will be understood that it is desirable to have high phosphate
binding capability over as broad a pH range as possible.
An alternate method of expressing phosphate binding capacity using
the method described above is to express the phosphate bound by the
binder as mmol of Phosphate bound per gram of binder.
Using this description for phosphate binding, suitably, the
water-insoluble inorganic solid phosphate binders used in the
tablets of the present invention have a phosphate binding capacity
at a pH from 3 to 6, preferably at a pH from 3 to 9, more
preferably at a pH from 3 to 10, most preferably at a pH from 2 to
10 as measured by the above method of at least 0.3 mmol/g after 30
minutes, preferably at least 0.3 mmol/g after 10 minutes, more
preferably at least 0.3 mmol/g after 5 minutes. Preferably the
water-insoluble inorganic solid phosphate binders used in the
tablets of the present invention have a phosphate binding capacity
at a pH from 3 to 4, preferably from 3 to 5, more preferably from 3
to 6 as measured by the above method of at least 0.4 mmol/g after
30 minutes, preferably at least 0.4 mmol/g after 10 minutes, more
preferably at least 0.4 mmol/g after 5 minutes. Even more
preferably the water-insoluble inorganic solid phosphate binders
used in the tablets of the present invention have a phosphate
binding capacity at a pH from 3 to 4, preferably from 3 to 5, more
preferably from 3 to 6 as measured by the above method of at least
0.5 mmol/g after 30 minutes, preferably at least 0.5 mmol/g after
10 minutes, more preferably at least 0.5 mmol/g after 5
minutes.
Granules
The granules of the present invention comprise at least 50%,
preferably at least 60%, more preferably at least 70% most
preferably at least 75%, by weight inorganic phosphate binder.
The granules of the present invention comprise from 3 to 12% by
weight of non-chemically bound water, preferably from 5 to 10% by
weight.
The remainder of the granules comprises a pharmaceutically
acceptable carrier for the phosphate binder, chiefly an excipient
or blend of excipients, which provides the balance of the granules.
Hence the granules may comprise no greater than 47% by weight of
excipient. Preferably the granules comprise from 5 to 47% by weight
of excipient, more preferably from 10 to 47% by weight of
excipient, more preferably from 15 to 47% by weight of
excipient.
Granule Size
Suitably, at least 95% by weight of the granules have a diameter
less than 1180 micrometers as measured by sieving.
Preferably, at least 50% by weight of the granules have a diameter
less than 710 micrometers as measured by sieving.
More preferably, at least 50% by weight of the granules have a
diameter from 106 to 1180 micrometers, preferably from 106 to 500
micrometers.
Even more preferably, at least 70% by weight of the granules have a
diameter from 106 to 1180 micrometers, preferably from 106 to 500
micrometers.
Preferably the weight median particle diameter of the granules is
from 200 to 400 micrometers.
Larger granules can lead to unacceptably slow phosphate binding.
Too high a proportion of granules less than 106 micrometers in
diameter can lead to the problem of poor flowability of the
granules. Preferably, at least 50% by weight of the granules have a
diameter greater than 106 micrometers as measured by sieving, more
preferably at least 80% by weight.
Granule Ingredients
Suitable excipients which may be included in the granules include
conventional solid diluents such as, for example, lactose, starch
or talcum, as well as materials derived from animal or vegetable
proteins, such as the gelatins, dextrins and soy, wheat and
psyllium seed proteins; gums such as acacia, guar, agar, and
xanthan; polysaccharides; alginates; carboxymethylcelluloses;
carrageenans; dextrans; pectins; synthetic polymers such as
polyvinylpyrrolidone; polypeptide/protein or polysaccharide
complexes such as gelatin-acacia complexes; sugars such as
mannitol, dextrose, galactose and trehalose; cyclic sugars such as
cyclodextrin; inorganic salts such as sodium phosphate, sodium
chloride and aluminium silicates; and amino acids having from 2 to
12 carbon atoms such as a glycine, L-alanine, L-aspartic acid,
L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and
L-phenylalanine.
The term excipient herein also includes auxiliary components such
as tablet structurants or adhesives, disintegrants or swelling
agents.
Suitable structurants for tablets include acacia, alginic acid,
carboxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, dextrin, ethylcellulose, gelatin, glucose,
guar gum, hydroxypropylmethylcellulose, kaltodectrin,
methylcellulose, polyethylene oxide, povidone, sodium alginate and
hydrogenated vegetable oils.
Suitable disintegrants include cross-linked disintegrants. For
example, suitable disintegrants include cross-linked sodium
carboxymethylcellulose, cross-linked hydroxypropylcellulose, high
molecular weight hydroxypropylcellulose, carboxymethylamide,
potassium methacrylatedivinylbenzene copolymer,
polymethylmethacrylate, cross-linked polyvinylpyrrolidone (PVP) and
high molecular weight polyvinylalcohols.
Cross-linked polyvinylpyrrolidone (also known as crospovidone, for
example available as Kollidon CL-M.TM. ex BASF) is an especially
preferred excipient for use in the tablets of the invention.
Suitably, the granules of the tablets of the invention comprise
from 1 to 15% by weight of cross-linked polyvinylpyrrolidone,
preferably from 1 to 10%, more preferably from 2 to 8%. Preferably,
the cross-linked polyvinylpyrrolidone has a d.sub.50 weight median
particle size, prior to granulation of less than 50 micrometers
(i.e. so-called B-type cross-linked PVP). Such material is also
known as micronised crospovidone. It has been found that the
cross-linked polyvinylpyrrolidone at these levels leads to good
disintegration of the tablet but with less inhibition of phosphate
binding of the inorganic phosphate binder as compared to some other
excipients. The preferred sizes for the cross-linked
polyvinylpyrollidone give reduced grittiness and hardness of the
particles formed as the tablets disintegrate.
Another preferred excipient for use in the granules of the tablets
of the invention is pregelatinised starch (also known as pregelled
starch). Preferably, the granules comprise from 5 to 20% by weight
of pregelled starch, more preferably 10 to 20%, even more
preferably from 12 to 18% by weight. The pregelatinised starch at
these levels improves the durability and cohesion of the tablets
without impeding the disintegration or phosphate binding of the
tablets in use. The pregelatinised starch is suitably fully
pregelatinised, with a moisture content from 1 to 15% by weight and
a weight median particle diameter from 100 to 250 micrometers. A
suitable material is Lycotab.TM.--a fully pregelatinised maize
starch available from Roquette.
A combined excipient including both pregelatinised starch and
crospovidone is particularly preferred, as this combination of
excipients gives the ability to reliably form compacted tablets of
various shapes, good granule homogeneity and good disintegration
characteristics from the granules of the invention.
The granules may also comprise preservatives, wetting agents,
antioxidants, surfactants, effervescent agents, colouring agents,
flavouring agents, pH modifiers, sweeteners or taste-masking
agents. Suitable colouring agents include red, black and yellow
iron oxides and FD & C dyes such as FD & C blue No. 2 and
FD & C red No. 40 available from Ellis & Everard. Suitable
flavouring agents include mint, raspberry, liquorice, orange,
lemon, grapefruit, caramel, vanilla, cherry and grape flavours and
combinations of these. Suitable pH modifiers include sodium
hydrogencarbonate (i.e. bicarbonate), citric acid, tartaric acid,
hydrochloric acid and maleic acid. Suitable sweeteners include
aspartame, acesulfame K and thaumatin. Suitable taste-masking
agents include sodium hydrogencarbonate, ion-exchange resins,
cyclodextrin inclusion compounds and adsorbates. Suitable wetting
agents include sodium lauryl sulphate and sodium docusate. A
suitable effervescent agent or gas producer is a mixture of sodium
bicarbonate and citric acid.
Granulation
Granulation may be performed by a process comprising the steps of:
i) mixing the solid water-insoluble inorganic compound capable of
binding phosphate with one or more excipients to produce a
homogeneous mix, ii) contacting a suitable liquid with the
homogeneous mix and mixing in a granulator to form wet granules,
iii) optionally passing the wet granules though a screen to remove
granules larger than the screen size, iv) drying the wet granules
to provide dry granules. v) milling and/or sieving the dry
granules.
Suitably the granulation is by wet granulation, comprising the
steps of; i) mixing the inorganic solid phosphate binder with
suitable excipients to produce a homogeneous mix, ii) adding a
suitable liquid to the homogeneous mix and mixing in a granulator
to form granules, iii) optionally passing the wet granules though a
screen to remove granules larger than the screen size, iv) drying
the granules. v) milling and sieving the granules
Suitable liquids for granulation include water, ethanol and
mixtures thereof. Water is a preferred granulation liquid.
The granules are dried to the desired moisture levels as described
hereinbefore prior to their use in tablet formation or
incorporation into a capsule for use as a unit dose.
Lubricant
Prior to tabletting the granules into a unit dose composition, it
is preferred that the granules are blended with a lubricant or
glidant such that there is lubricant or glidant distributed over
and between the granules during the compaction of the granules to
form tablets.
Typically the optimum amount of lubricant required depends on the
lubricant particle size and on the available surface area of the
granules. Suitable lubricants include silica, talc, stearic acid,
calcium or magnesium stearate and sodium stearyl fumarate and
mixtures thereof. Lubricants are added to the granules in a finely
divided form, typically no particles greater than 40 micrometers in
diameter (ensured typically by sieving). The lubricant is suitably
added to the granules at a level of from 0.1 to 0.4%, preferably
from 0.2 to 0.3% by weight of the granules. Lower levels can lead
to sticking or jamming of the tablet die whereas higher levels may
reduce the rate of phosphate binding or hinder tablet
disintegration. Salts of fatty acids may be used as lubricants,
such as calcium and/or magnesium stearate. A preferred lubricant is
selected from the group consisting of magnesium stearate, sodium
stearyl fumarate and mixtures thereof. It has been found that some
lubricants, such as fatty acids, lead to pitting and loss of
integrity in the coating layer of the tablets. It is thought that
this may arise from partial melting of the lubricant as the coating
layer is dried. Hence it is preferred that the lubricant has a
melting point in excess of 55.degree. C.
Tablets
The tablets of the third aspect of invention may be prepared by
compressing granules, under high pressure, in order to form a
tablet having the necessary crushing strength for the handling
required during packaging and distribution. The use of granules
formed from a granulated powder mixture improves flowability from
storage hoppers to the tabletting press which in turn benefits the
efficiency of tablet processing. The inorganic phosphate binders
used in the tablets of the present invention typically have poor
flowability properties at their desired particle size as detailed
hereinbefore. Because it is desired that the tablets of the
invention comprise high levels of inorganic phosphate binder, of
the order of 50% or more by weight of the tablet, the inorganic
phosphate binder must be formed into granules prior to tablet
formation. A fine powder is apt to pack or "bridge" in the hopper,
feed shoe or die, and thus tablets of even weight or even
compression are not easily obtainable. Even if it were possible to
compress fine powders to a satisfactory degree, air may be trapped
and compressed, which may lead to splitting of the tablet on
ejection. The use of granules helps to overcome these problems.
Another benefit of granulation is the increase in bulk density of
the final tablet when prepared from granules rather than from fine
powder, reducing the size of the final tablet and improving the
likelihood of patient compliance.
The tablets of the invention may be circular but are preferably
generally bolus- or torpedo-shaped (also known as double convex
oblong shaped tablet) i.e. having an elongate dimension, in order
to assist swallowing of larger doses. It may for example be in the
form of a cylinder with rounded ends or elliptical in one dimension
and circular in an orthogonal dimension, or elliptical in both.
Some flattening of one or more parts of the overall shape is also
possible.
Where the tablet is in the form of a tablet provided with a
"belly-band", it is preferred if the width of the belly-band is 2
mm or more. It has been found that smaller belly-bands can lead to
insufficient coverage or chipping or loss of integrity of the
water-resistant coating of the tablet.
The tablets of the second aspect of the invention preferably have a
hardness from 5 to 30 kgf as measured using a Holland C50 tablet
hardness tester.
Water Resistant Coating
The tablets of the second aspect of the invention, once formed from
the granules of the first aspect of the invention, are preferably
provided with a water-resistant coating.
The water-resistant coating may be applied to the tablet by any of
the usual pharmaceutical coating processes and equipment. For
example, tablets may be coated by fluid bed equipment (for example
a "Wurster" type fluid bed dryer) coating pans (rotating, side
vented, convention etc), with spray nozzles or guns or other
sprayer types or by dipping and more recent techniques including
Supercell tablet coater from Niro PharmaSystems. Variations in
available equipment include size, shape, location of nozzles and
air inlets and outlets, air flow patterns and degree of
instrumentation. Heated air may be used to dry the sprayed tablets
in a way that allows continuous spraying while the tablets are
being simultaneously dried. Discontinuous or intermittent spraying
may also be used, but generally requires longer coating cycles. The
number and position of nozzles may be varied, as needed depending
on the coating operation and the nozzles(s) is preferably aimed
perpendicularly or nearly perpendicular to the bed although other
direction(s) of aim may be employed if desired. A pan may be
rotated at a speed selected from a plurality of operating speeds.
Any suitable system capable of applying a coating composition to a
tablet may be used. Virtually any tablet is acceptable herein as a
tablet to be coated. The term "tablet" could include tablet, pellet
or pill. Typically the preferred tablet will be in a form
sufficiently stable physically and chemically to be effectively
coated in a system which involves some movement of a tablet, as for
example in a fluidized bed, such as in a fluidized bed dryer or a
side vented coating pan, combinations thereof and the like. Tablets
may be coated directly, i.e. without a subcoat to prepare the
surface. Subcoats or topcoats may of course be used. If desired,
the same or a similar coating application system can be employed
for both a first or second or more coating applications. The
coating composition is prepared according to the physical
properties of its constituents, i.e. soluble materials are
dissolved, insoluble materials are dispersed. The type of mixing
used is also based on the properties of the ingredients. Low shear
liquid mixing is used for soluble materials and high shear liquid
mixing is used for insoluble materials. Usually the coating
formulation consists of two parts, the colloidal polymer suspension
and the pigment suspension or solution (eg red oxide or Quinoline
yellow dye). These are prepared separately and mixed before
use.
A wide range of coating materials may be used, for example,
cellulose derivatives, polyvinylpyrrolidone, polyvinyl alcohol,
polyvinyl acetate, polyethylene glycols, copolymers of styrene and
acrylate, copolymers of acrylic acid and methacrylic acid,
copolymers of methacrylic acid and ethylacrylate, copolymers of
methyl methacrylate and methacrylate, copolymers of methacrylate
and tertiary amino alkyl methacrylate, copolymers of ethylacrylate
methyl methacrylate and quaternary amino alkyl methacrylate and
combinations of two or more hereof. Preferably, salts of
methacrylate copolymers are used, eg. butylated methacrylate
copolymer (commercially available as Eudragit EPO).
The coating is suitably present as 0.05 to 10% by weight of the
coated tablet, preferably from 0.5% to 7%. Preferably the coating
material is used in combination with red iron oxide pigment
(Fe.sub.2O.sub.3) (1% or more, preferably 2% or more by weight of
the dried coating layer) which is dispersed throughout the coating
material and provides an even colouring of the coating layer on the
tablet giving a pleasant uniform appearance.
In addition to protecting the tablet core from moisture loss or
ingress on storage, the water resistant coating layer also helps to
prevent the rapid breakup of the tablet in the mouth, delaying this
until the tablet reaches the stomach. With this purpose in mind, it
is preferred if the coating material has low solubility in alkaline
solution such as found in the mouth, but more soluble in neutral or
acid solution. Preferred coating polymers are salts of methacrylate
copolymers, particularly butylated methacrylate copolymer
(commercially available as Eudragit EPO). Preferably the coating
layer comprises at least 30% by weight of a coating polymer, more
preferably at least 40% by weight.
The water loss or uptake of coated tablets is suitably measured as
detailed hereinbefore for the measurement of the non-chemically
bound water content for granules. From a set of freshly prepared
coated tablets, some are measured for non-chemically bound water
immediately following preparation, and others are measured after
storage as detailed above.
In another aspect, the invention provides a method for preparing a
tablet according to the first aspect of the invention, the method
comprising granulating a water-insoluble inorganic solid phosphate
binder with a pharmaceutically acceptable excipient and optionally,
any other ingredients, forming a tablet from the granules by
compression and optionally applying a water-resistant coating to
the tablet so formed.
Capsules
Suitable capsules for use in the second aspect of the invention are
hard gelatine capsules, although other suitable capsule films may
be used.
Use of Unit Doses
For treatment of and prophylaxis of hyperphosphataemia, amounts of
from 0.1 to 500, preferably from 1 to 200, mg/kg body weight of
inorganic phosphate binder are preferably administered daily to
obtain the desired results. Nevertheless, it may be necessary from
time to time to depart from the amounts mentioned above, depending
on the body weight of the patient, the animal species of the
patient and its individual reaction to the drug or the kind of
formulation or the time or interval in which the drug is applied.
In special cases, it may be sufficient to use less than the minimum
amount given above, whilst in other cases the maximum dose may have
to be exceeded. For a larger dose, it may be advisable to divide
the dose into several smaller single doses. Ultimately, the dose
will depend upon the discretion of the attendant physician.
Administration before meals, e.g. within one hour before a meal is
suitable. Alternatively, the dose may be taken with a meal.
A typical tablet of the invention for human adult administration
may comprise from 1 mg to 5 g, preferably from 10 mg to 2 g, more
preferably from 100 mg to 1 g, such as from 150 mg to 750 mg, from
200 mg to 750 mg or from 250 mg to 750 mg of water-insoluble
inorganic solid phosphate binder.
Preferably the unit doses of the invention comprise at least 200 mg
of a water-insoluble solid inorganic phosphate binder. Preferably
the unit doses of the invention comprise at least 250 mg of a
water-insoluble solid inorganic phosphate binder Preferably the
unit doses of the invention comprise at least 300 mg of a
water-insoluble solid inorganic phosphate binder. A more preferred
unit dose comprises 500 mg of the phosphate binder. The preferred
unit dose weight is less than 750 mg, more preferably less than 700
mg, to aid with patient compliance for oral dosage. A particularly
preferred unit dose contains 200 mg (.+-.20 mg) of a
water-insoluble solid inorganic phosphate binder. A particularly
preferred unit dose contains 250 mg (.+-.20 mg) of a
water-insoluble solid inorganic phosphate binder. A particularly
preferred unit dose contains 300 mg (.+-.20 mg) of a
water-insoluble solid inorganic phosphate binder. When the unit
dose is a tablet, the preferred unit dose weight includes any
optional coating.
The tablet forms may be packaged together in a container or
presented in foil strips, blister packs or the like, e.g. marked
with days of the week against respective doses, for patient
guidance.
In the further aspects of the invention detailed below, granular
material refers to the granules of the first aspect of the
invention.
An aspect of the invention is the granular material for use in or
as a medicine on humans or animals, particularly as a medicine for
the binding of phosphate, more particularly for the treatment of
hyperphosphataemia.
Another aspect is the use of the granular material in the
manufacture of a medicament for use on animals or humans in the
treatment or therapy of a condition or disease associated with
adverse phosphate levels, particularly elevated plasma phosphate
levels, particularly hyperphosphataemia.
Another aspect is a method for the treatment or therapy of a
condition or disease associated with adverse phosphate levels,
particularly elevated plasma phosphate levels, particularly
hyperphosphataemia by oral administration of the granular material
to humans or animals.
Storage
As discussed herein, we have found that the system of the present
invention can provide tablets which are stable of over a period of
at least 12 months (see Table 7 for particle size of small and
large granules) determined at 25 C/60RH and 30 C/65RH. Under more
extreme storage conditions (40 C/75RH) the storage stability is at
least 6 months for both granule types.
Further Aspects
Further aspects of the present invention are described in the
following numbered paragraphs: 1. Granules comprising at least 50%
by weight of water-insoluble inorganic solid phosphate binder, from
3 to 12% by weight of non-chemically bound water and up to 47% by
weight of excipient. 2. Granules according to paragraph 1 wherein
the water-insoluble inorganic solid phosphate binder is a mixed
metal compound. 3. Granules according to paragraph 2, wherein the
mixed metal compound is a compound of formula (I):
M.sup.II.sub.1-XM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.zH.sub.2O
(I) where M.sup.II is at least one bivalent metal; M.sup.III is at
least one trivalent metal; A.sup.n- is at least one n-valent anion;
x=.SIGMA.ny and x, y and z fulfil 0<x.ltoreq.0.67,
0<y.ltoreq.1, 0.ltoreq.z.ltoreq.10. 4. Granules according to
paragraph 3 wherein x=.SIGMA.ny and x, y and z fulfil
0<x.ltoreq.0.5, 0<y.ltoreq.1, 0.ltoreq.z.ltoreq.10. 5.
Granules according to any one of paragraphs 2 to 4 wherein the
mixed metal compound is free from Aluminium and contains the metals
iron(III) and at least one of Magnesium, Calcium, Lanthanum or
Cerium. 6. Granules according to any one of paragraphs 3 to 5
wherein the mixed metal compound of formula (I) is a layered double
hydroxide. 7. Granules according to any one of paragraphs 3 to 6
wherein the mixed metal compound contains at least one of hydroxyl
and carbonate ions and contains as the metals iron (III) and
magnesium. 8. Granules according to any one of paragraphs 1 to 7,
wherein the granules comprise from 5 to 15% by weight of polyvinyl
pyrrolidone as an excipient. 9. Granules according to any one of
paragraphs 1 to 8, comprising from 10 to 20% by weight of
pregelatinised starch as an excipient. 10. Granules according to
any one of paragraphs 1 to 9 wherein the granules have a diameter
less than 1000 micrometers. 11. A unit dose for oral administration
comprising a water resistant capsule containing granules according
to any preceding paragraph. 12. A unit dose for oral administration
comprising a compacted tablet of granules according to any of
paragraphs 1 to 10. 13. A unit dose according to paragraph 12
further comprising a lubricant between the granules. 14. A unit
dose according to paragraph 13 comprising magnesium stearate as
lubricant between the granules. 15. A unit dose according to any
one of paragraphs 12 to 14 coated with a water-resistant coating.
16. A unit dose according to paragraph 15 wherein the
water-resistant coating comprises at least 30% by weight of a
butylated methacrylate copolymer. 17. A unit dose according to any
one of paragraphs 12 to 16 wherein the tablet is provided with a
belly band having a width of 2 mm or more. 18. A unit dose
according to any one of paragraphs 11 to 17 comprising at least 300
mg of a water-insoluble inorganic solid phosphate binder. 1A. A
granular material comprising (i) at least 50% by weight based on
the weight of the granular material of solid water-insoluble
inorganic compound capable of binding phosphate, (ii) from 3 to 12%
by weight based on the weight of the granular material of
non-chemically bound water, and (iii) no greater than 47% by weight
based on the weight of the granular material of excipient. 2A. A
granular material according to paragraph 1A wherein the
water-insoluble inorganic solid phosphate binder is a mixed metal
compound. 3A. A granular material according to paragraph 2A,
wherein the mixed metal compound is a compound of formula (I):
M.sup.II.sub.1-xM.sup.III.sub.x(OH).sub.2A.sup.n-.sub.y.zH.sub.2O
(I) where M.sup.II is at least one bivalent metal; M.sup.III is at
least one trivalent metal; A.sup.n- is at least one n-valent anion;
x=.SIGMA.ny; 0<x.ltoreq.0.67, 0<y.ltoreq.1, and
0.ltoreq.z.ltoreq.10. 4A. A granular material according to
paragraph 3A wherein x=.SIGMA.ny; 0<x.ltoreq.0.5,
0<y.ltoreq.1, and 0.ltoreq.z.ltoreq.10. 5A. A granular material
according to paragraph 3A or 4A wherein the mixed metal compound of
formula (I) is a layered double hydroxide. 6A. A granular material
according to any one of paragraphs 2A to 5A wherein the mixed metal
compound contains at least one of hydroxyl and carbonate ions and
contains as the metals iron (III) and magnesium. 7A. A granular
material according to any one of paragraphs 1A to 6A wherein the
water-insoluble inorganic compound is free from Aluminium. 8A. A
granular material according to any one of paragraphs 1A to 7A
wherein the water-insoluble inorganic compound contains iron(III)
and at least one of Magnesium, Calcium, Lanthanum or Cerium. 9A. A
granular material according to any one of paragraphs 1A to 8A,
wherein the granular material comprises from 5 to 20% by weight of
pregelatinised starch as excipient based on the weight of the
granular material. 10A. A granular material according to any one of
paragraphs 1 to 9A, comprising from 1 to 15% by weight of polyvinyl
pyrrolidone as excipient based on the weight of the granular
material. 11A. A granular material according to any one of
paragraphs 1A to 10A wherein at least 95% by weight of the granules
of the granular material have a diameter less than 1180
micrometers. 12A. A unit dose for oral administration comprising a
water resistant capsule containing a granular material according to
any one of paragraphs 1A to 11A. 13A. A unit dose for oral
administration comprising a compacted tablet of a granular material
according to any of paragraphs 1A to 11A. 14A. A unit dose
according to paragraph 13A further comprising a lubricant between
the granules. 15A. A unit dose according to paragraph 14A wherein
the lubricant is or comprises magnesium stearate. 16A. A unit dose
according to any one of paragraphs 13A to 15A coated with a
water-resistant coating. 17A. A unit dose according to paragraph
16A wherein the water-resistant coating comprises at least 30% by
weight of a butylated methacrylate copolymer. 18A. A unit dose
according to any one of paragraphs 16A to 17A wherein the tablet
has a belly band having a width of 2 mm or more. 19A. A unit dose
according to any one of paragraphs 12A to 18A wherein the solid
water-insoluble inorganic compound capable of binding phosphate is
present in an amount of at least 300 mg. 20A. A process for the
preparation of a granular material as defined in any one of
paragraphs 1A to 11A comprising the steps of: i) mixing the solid
water-insoluble inorganic compound capable of binding phosphate
with one or more excipients to produce a homogeneous mix, ii)
contacting a suitable liquid with the homogeneous mix and mixing in
a granulator to form wet granules, iii) optionally passing the wet
granules though a screen to remove granules larger than the screen
size, iv) drying the wet granules to provide dry granules. v)
milling and/or sieving the dry granules. 21A. A process according
to paragraph 20A where in the liquid is selected from water,
ethanol and mixtures thereof. 22A. A granular material according to
any one of paragraphs 1A to 11A for use in medicine. 23A. Use of a
granular material according to any one of paragraphs 1A to 11A in
the manufacture of a medicament for binding of phosphate. 24A. Use
of a granular material according to any one of paragraphs 1A to 11A
in the manufacture of a medicament for use in the therapy of a
condition or disease associated with phosphate levels. 25A. Use of
a granular material according to any one of paragraphs 1A to 11A in
the manufacture of a medicament for use in the therapy of a
condition or disease associated with adverse phosphate levels. 26A.
Use of a granular material according to any one of paragraphs 1A to
11A in the manufacture of a medicament for use in the therapy of a
condition or disease associated with elevated plasma phosphate
levels. 27A. Use of a granular material according to any one of
paragraphs 1A to 11A in the manufacture of a medicament for use in
the therapy of hyperphosphataemia.
The present invention will now be explained in more detail by way
of the following non-limiting examples.
EXAMPLES
The phosphate binder used in the examples below was formed by the
reaction of aqueous solutions of magnesium sulphate and ferric
sulphate in the presence of sodium hydroxide and sodium carbonate.
The synthesis reaction is described by:
4MgSO.sub.4+Fe.sub.2(SO.sub.4).sub.3+12
NaOH+Na.sub.2CO.sub.3.fwdarw.Mg.sub.4Fe.sub.2(OH).sub.12.CO.sub.3.nH.sub.-
2O+7Na.sub.2SO.sub.4. The precipitation was carried out at
approximately pH 10.3 at ambient temperature (15-25.degree. C.).
The resulting precipitate was filtered, washed, dried, milled and
then sieved such that all material is less than 106 micron. The
formula of the phosphate binder was:
Mg.sub.4Fe.sub.2(OH).sub.12.CO.sub.3.nH.sub.2O and had the
following XRF composition: MgO=29.0%, Fe.sub.2O.sub.3=28.7%, Mg:Fe
mole ratio=2:1. The XRF values take into account all water present
in the phosphate binder. XRD showed that the phosphate binder was
characterised by the presence of the poorly crystalline
hydrotalcite type structure.
TABLE-US-00003 TABLE 1 Example Material 1 2 3 4 5 6 7 Granules
Phosphate Binder 75.1 65.0 66.1 56.3 74.9 75.1 74.9 Pre-gelled
Starch 14.1 14.0 9.4 14.1 9.4 Microcrystalline 28.5 37.7 Cellulose
Micronised 4.7 14.0 9.4 4.7 9.4 Crospovidone Water content (dried
5.8 6.7 5.1 5.7 6.0 5.8 6.0 granules) Lubricants used for
tabletting Stearic acid 0.3 0.3 0.3 0.3 0.3 Magnesium Stearate 0.3
0.3 All values in the tables are percentages by weight.
Granules were prepared using the formulations as detailed in Table
1. The dry blends were made in 125 ml batches by mixing the
components in the Turbula powder blender for 5 minutes prior to
granulation. The 125 gram batches of dry powder blend were
granulated by the steady addition of purified water in a planar
mixer until small, distinct granules were produced. Each of the
powder blends required different amounts of water to granulate.
Typical values of water used for granulation as weight percentage
of dry powder weight are: example (1)--106%, example (2)--111%,
example (3)--78%, example (4)--83%, example (5)--100%, example
(6)--70-106%, example (7)--78%. Batches of granules made for each
of the formulations were then combined and dried in a fluid bed
drier at an air inlet temperature of 40.degree. C. to a target
moisture content of 4-6% w/w before being passed through a 1.18 mm
aperture mesh to remove large granules.
The amount of water required to granulate varied dependent on
phosphate binder moisture content, particle size distribution,
feed-rate and degree of dispersion (water droplet size). Typically
if water was used at less than 50% finer granules were obtained
whereas excessive amounts of water (above 110%) resulted in lump
formation. The preferred water amount was between 70 and 100%.
Tablets were made with hardnesses from 13 to 29 kgF as measured by
a Holland C50 tablet hardness tester. Varying compaction pressures
were used to give tablets of differing tablet hardness (as measured
in Kg Force) as detailed in Table 2, from formulations 1 to 4. 0.3%
stearic acid was used as a lubricant.
The disintegration time for the tablets was measured using a
disintegration bath--Copley DTG 2000 IS.
The phosphate binding capacity in Table 2 was measured as detailed
in the phosphate binding test described hereinbefore at pH=4 and
time=30 minutes.
Friability was measured by tablet friability tester Erweka TA10
Results are shown in Table 2 for uncoated tablets prepared from
granules of formulae 1, 2, 3 and 4 at three differing crush
strengths (tablet hardness) (a,b and c) as indicated in the
table.
TABLE-US-00004 TABLE 2 Tablet Disintegration P (%) Hardness
Friability Example Time (sec) Binding (KgF) (%) 1a 25 61 13 0 1b 25
66 21 0 1c 50 64 25 0 2a 20 58 13 0 2b 40 60 21 0 2c 53 61 27 0 3a
15 65 16 0 3b 12 60 19 0 3c 15 61 29 0 4a 8 55 16 0 4b 12 57 21 0
4c 20 60 28 0
Table 3 shows the effect of the addition of a water-resistant
coating comprising Eudragit EPO on tablets prepared from granules
of the formulation of example 1.
The coating formulation is:
84.02% Purified water, 0.81% Sodium Dodecyl Sulphate, 8.08%
Butylated methacrylate Copolymer (Eudragit EPO), 1.21% Stearic
acid, 2.09% Talc, 2.83% MgStearate, 0.64% Titanium dioxide, 0.32%
Red iron oxide. The coating was dried after application using hot
air at 48.degree. C.
Coating levels disclosed herein are determined from the increase in
tablet weight before and after application of the coating
formulation and drying in hot-air at 48.degree. C.
TABLE-US-00005 TABLE 3 Coating Level Disintegration (% weight of
coated tablet) Time (s) 0.69 45 2.34 45-59 2.83 51-63 4.39
80-140
From Table 3 it can be seen that a coating has the effect of
delaying the disintegration of the tablets.
Table 4 shows the effect of different coating type and lubricants
on the storage behaviour and tablet characteristics for tablets
formed with a hardness of 10 to 15 kgF from the granules of
examples 1, 5, 6 and 7. Tablets from examples 1 and 5 included 0.3%
by weight stearic acid as lubricant. Tablets from examples 6 and 7
included 0.3% by weight of Magnesium Stearate as lubricant.
TABLE-US-00006 TABLE 4 Moisture content Disintegration (%)
Appearance Time(s) (coated tablet) (Visible Pitting) Example
initial 4 weeks Initial 4 weeks initial 4 weeks Ex1 158 226 8.6
12.7 No Yes Eudragit Ex 6 422 128 8.8 11.3 No No Eudragit Ex 6 107
49 8.5 10.8 No Yes Opadry-AMB Ex 5 139 14 7.7 11.5 No Yes Eudragit
Ex 7 122 62 9.6 11.9 No No Eudragit Ex 7 72 27 8.5 11.1 No Yes
Opadry-AMB
The Eudragit coating is as described above
The Opadry AMB coating has Opaglos 2 Sodium Carboxymethylcellulose
replacing Eudragit EPO as coating polymer with other coating
ingredients as for the Eudragit coating composition.
Note that the moisture content in Table 4 is that for the complete
coated tablet and not for the granules.
Storage was carried out with the tablets openly exposed at
75.degree. C. and 40% relative humidity for 4 weeks.
From Table 4 it can be seen that the Opadry coating does not
prevent pitting on storage with Mg Stearate lubricant, whereas the
Eudragit does. Even the Eudragit does not prevent pitting with
Stearic acid. Hence the optimal system is Mg Stearate lubricant
with Eudragit Coating.
Table 5 shows the effect of granule size and moisture content on
the tablet disintegration time of an uncoated tablet in water at pH
7 and in 0.1 Normal HCl both at 37.degree. C. The formulation was
as for example 6 (but with varying levels of moisture) The tablets
were compacted to the same approximate hardness of 10-15 Kgf.
TABLE-US-00007 TABLE 5 Granule Disintegration Disintegration
Granule diameter Time (s) Time(s) moisture(%) (.mu.m) Water 0.1N
HCl Comments 1.19 <425 16 20 Static charge dusty 1.19 <1180
34 41 Static charge dusty 7.01 <425 20 24 Good 7.01 <1180 46
51 Good 18.84 <425 1090 1214 Irregular tablet surface 18.84
<1180 784 976 Irregular tablet surface
The irregular tablet surface for the high moisture granules was due
to excess material squeezing past the sides of the tablet die
during compaction.
All granules were sieved such that less than 25% by weight of the
granules had a diameter less than 106 micrometers by sieving.
From Table 5 it can be seen that increasing the granule size slows
disintegration at granule moisture levels of 1.19 and 7.01%, and
that the moisture content has a marked effect on both
disintegration time and tablet quality.
A similar effect was found for the effect of granule size on the
retardation of phosphate binding. Tablets formed from granules
according to example 6 having a diameter less than 1180 .mu.m were
compared for phosphate binding as a function of time against
tablets formed from granules having a diameter less than 425 .mu.m.
The tablets were both compacted to a strength of 13 kg tablet
hardness and were coated with 4.5% of dried Eudragit EPO water
resistant coating. The tablets prepared from the smaller granules
reached 80% of the equilibrium phosphate binding after 10 minutes,
whereas the tablets prepared from the larger granules took 30
minutes. The equilibrium phosphate binding is as measured after 120
minutes. The phosphate binding results were obtained according to
the modified method as described hereafter.
Table 6 shows phosphate binding of coated tablets formed from
granules according to Example 6 coated with Eudragit EPO in an
amount of 4.5 wt % based on the coated tablet, the granules having
a diameter less than 425 micrometers.
Table 6, 7 and 8 show phosphate binding (expressed as mmol of
phosphate bound per gram of solid inorganic phosphate binder) at
various pH values for the solution in which binding was
measured.
The results of Table 6, 7, and 8 were obtained by means of the
phosphate binding method described hereinbefore, but with the
following modifications: 1 tablet containing 0.5 g of the phosphate
binder was dispersed in 125 ml of 4 mmol/liter phosphate solution
(as opposed to 12.5 ml of 40 mmol/liter). The samples were then
incubated in stoppered polypropylene conical flasks in a shaking
water bath at 37.degree. C. and 200 rpm for varying times. pH of
the phosphate solution was varied using 1M NaOH or HCl solution.
The calibration standards for the ICP-OEC were changed accordingly
to take account of the lower phosphate concentration.
TABLE-US-00008 TABLE 6 phosphate binding (mmol/g) at different
times (minutes) Time pH 10 30 60 120 3 0.44 0.54 0.56 0.59 4 0.44
0.5 0.53 0.55 9 0.25 0.33 0.35 0.38
Table 7 shows the effect of particle size distribution for the
granules on various parameters. "Transport" refers to the ease of
transfer from a hopper to the tablet press in relation to jamming
and bridging. The granules were formed according to example 6. The
fine granules (A) were poor.
Phosphate binding was measured by means of the phosphate binding
method described previously as for Table 6 at a pH of 4.
The Phosphate binding results for A, B, C and D were from tablets
(uncoated) whereas the results for E were from the granules
themselves.
TABLE-US-00009 TABLE 7 particle size fine small large large medium
by sieving A B C D E (micrometres) 0 100 100 100 100 100 53 32 94
98 92 96 106 25 83 96 87 91 250 9 49 90 76 500 3 0 71 51 47 710 1 0
46 17 1180 0 0 5 3 0 Transport poor good good good good Phosphate
binding (minutes) 10 0.52 0.42 0.33 0.3 20 0.47 0.40 30 0.54 0.50
0.44 0.4 0.42 45 0.51 0.47 60 0.54 0.54 0.48 0.45 0.49 120 0.57
0.56 0.51 0.47
Examples 1-7 in uncoated tablet form, and prepared from granules
having a diameter less than 1180 micrometers, were also measured
using the modified phosphate binding test as shown in Table 8 at
pH=4 and time=30 minutes.
TABLE-US-00010 TABLE 8 Example 1 mmol PO4/g Example 2 Example 3
Example 6 Example 7 0.45 0.55 0.27 0.44 0.60
From Table 8 and comparison of example 2 with 3 it can be seen that
example 3 has lower phosphate binding demonstrating the effect of
hindering of phosphate binding by the presence of the
microcrystalline cellulose and the advantage of using the preferred
combination of pre-gelled starch and micronised crospovidone. This
preferred combination of excipients maintained good phosphate
binding as well as aiding the granulation process and showing good
dispersion of the granules and tablets in water.
Material from coated tablets (containing 0.5 g of binder) formed
from granules according to example 6 having diameters less than 425
micrometers was found to have the following Langmuir constants: K1
(1/mmol)=0.25 and K2 (mmol/g)=1.88.
Material from coated tablets (containing 0.5 g of binder) formed
from granules according to example 6 having diameters less than
1000 micrometers was found to have the following Langmuir
constants: K1 (1/mmol)=0.19 and K2 (mmol/g)=1.88.
K1 is the affinity constant and is an indication of the strength of
phosphate binding while K2 is the capacity constant and is the
maximum amount of phosphate that can be bound per unit weight of
binder.
These Langmuir constants were determined by changing the phosphate
concentration from 1 to 40 mmol/l and were calculated by performing
linear regression on a plot of the unbound/bound phosphate versus
the unbound phosphate measured at equilibrium. The initial pH of
the phosphate solutions was pH=4, temp=37 Celsius and the selected
equilibrium point was at a time t=120 minutes.
All publications and patents and patent applications mentioned in
the above specification are herein incorporated by reference.
Various modifications and variations of the present invention will
be apparent to those skilled in the art without departing from the
scope and spirit of the invention. Although the invention has been
described in connection with specific preferred embodiments, it
should be understood that the invention as claimed should not be
unduly limited to such specific embodiments. Indeed, various
modifications of the described modes for carrying out the invention
which are obvious to those skilled in chemistry, biology or related
fields are intended to be within the scope of the following
claims.
* * * * *
References